The goal of this project is to create DNA nanoparticles that specifically bind to Chronic Lymphocytic Leukemia (CLL) cells, which could then be used for diagnostic testing, in vivo targeting, and drug delivery. Our research group has developed a technology that utilizes rolling circle amplification (RCA) of circular oligonucleotide templates containing random nucleotides to produce libraries of single-stranded DNA, with each particle in the library containing hundreds of copies of its template, and each library containing over 10 billion unique particles. We have already had success generating nanoparticles against human dendritic cells, the mouse pancreatic cell line, Panc-02, and the human breast cancer cell line, MDA-MB- 231, and we have recently selected our first particles that bind CLL. In Aim 1, we will optimize the size of our particles for use in vivo and assess their biodistribution. In im 2, we will obtain blood samples from CLL patients and perform selections, counter-selections, and mock-selections, followed by high-throughput sequencing to determine the hierarchy of particles in the selection process. In Aim 3, we will utilize two xenograft models for CLL to perform additional selections in vivo, as this method will allow for selection of particles that function and target well in the body. We will use particles selected in this project to detect minimal residual disease in patient samples and we will test drug- loaded specific particles for effectiveness in mice.